Among development of drug polymorphs, two kinds of research way are the preferable way to be commonly used, one named multiple crystal selecting, while the other named being salt selecting. Multiple crystal selecting is that using some certain method to make the compound to form polymorphs in multiple different solvents. The common used method in multiple crystal selecting are: suspended balance method, solvent heating cooling method, saturated solution naturally evaporated method, anti-solvent adding method. Being salt selecting is that drugs reacted with different anti-ions (acid or base) to form a salt, in the reaction, the force between drugs with the acid or salt is primarily ion bond forms to produce reaction and effect.
darunavir, with chemical name [(1R,5S,6R)-2,8-bioxy biocyclo[3.3.0]-decane-6-yl]-N-[(2S,3R)-4-[(4-amino phenyl)sulfonyl-(2-methyl propyl)amino]-3-hydroxyl-1-phenyl-butane-2-yl] carbamic acid ester,

Darunavir is an inhibitor of protease, marketed with its ethanolate form in U.S.A in July 2006, the market name is Prezista. Darunavir exists in polymorphs, many manufactures have done much research work in it including its drug polymorphs and amorphous. Also, patent applications are filed about this product.
For example in WO2011048604 (applicant: MATRIX LABORATORIES LIMITED, publication date: Apr. 28, 2011), amorphous darunavir is obtained through a method of evaporation and concentration process. The detailed can be described as the following procedure, in a solvent such as ethyl acetate, darunavir was dissolved in, removing the solvent by concentration to form semi-solid, the hydro carbon solvent such as heptane was added, the amorphous darunavir crystal can be obtained after isolating. Usually, some drawbacks are existed when evaporation and concentration method are used: first is material easily to be bulked, special vacuum equipment need to be used in commercialized industry production, it can lead to the decrease of capacity; second is after the commercialized industry production, with the increase of solvent amount, it can lead to long time distillation process and also production cycle period lengthened accordingly. What's more, large amounts of waste gases are produced during evaporation and concentration process.
For example, in WO2013114382 (Applicant: MYLAN LABORATORIES LTD, publication date: Aug. 8, 2013), it took the following synthesis steps, in the solvent of acetate ester, darunavir was dissolved in, then adding heptane in to it as the anti-solvent, the anhydrate darunavir crystal was obtained. Although the application also uses the anti-solvent method, and no evaporation and concentration method defects existed, the solvent-free darunavir crystal was produced, not an amorphous form disclosed in the present application.
The present invention provides a preparation method for preparing amorphous form of darunavir using an anti-solvent method. It can be a different method compared to the evaporation and concentration process disclosed in WO2011048604. Although the same with WO2013114382, anti-solvent are used, the target crystal form are truly different. The crystal form of WO2013114382 is solvent-free darunavir crystal, while an amorphous form of darunavir in the present application.